5,12-epoxy-naphthacene-6,11-dione derivatives

ABSTRACT

There is provided a novel method of synthesizing certain tetracyclic quinones. In particular, there is provided a novel route to the synthesis of (+)-7-deoxydaunomycinone and analogs thereof which includes the provision of novel tetrahydronaphthoquinones and tetracyclic quinone intermediates. The compounds of the present invention are provided through a route comprising a Diels-Alder addition of certain isobenzofurans to certain novel tetrahydronaphthoquinones. The products of the synthetic route provided herein may be converted into compounds of known antibiotic and antineoplastic activity.

The invention described herein was made in the course of work under agrant or award from the Department of Health, Education and Welfare.

BACKGROUND OF THE INVENTION

Certain antibiotics having antineoplastic activity -- for example,adriamycin and related compounds -- are known in the art. Adriamycin isdescribed as being obtained by a microbiological process in U.S. Pat.No. 3,590,028 to Arcamone et al. Certain semi-synthetic procedures formaking these compounds are described in U.S. Pat. No. 3,803,124 also toArcamone et al. Certain synthetic intermediates -- in particular, thosedirected to the preparation of daunomycin and 4-demethoxydaunomycin --are disclosed in U.S. Pat. No. 3,963,760 to Bernardi and Patelli. Otherrelated compounds are disclosed by Patelli et al. in Belgian Pat. No.830,090 assigned to Societa Farmaceutici Italia S.p.A. A total syntheticroute to daunomycin is disclosed in application Ser. No. 632,939 of thepresent applicants with another co-worker now U.S. Pat. No. 4,070,381and a related synthetic sequence directed to the 4-demethoxydaunomycinand, inter alia, dimethyl-4-demethoxydaunomycin are disclosed in U.S.Pat. No. 4,021,457 of May 3, 1977 to the same applicants.

SUMMARY OF THE INVENTION

There is provided a novel process for the preparation of certainpolycyclic quinones -- in particular, tetracyclic quinones -- wherebythere is provided a route to the synthesis of 7-deoxydaunomycinone,7-deoxy-4-demethoxydaunomycinone, and 7-deoxy-4-demethoxy-methyl, and-dimethyldaunomycinone. The synthetic sequence comprises the Diels-Alderaddition of the appropriate isobenzofuran to a noveltetrahydronaphthoquinone to provide a tetracyclic quinone which isconverted, in four steps, to the desired known intermediate.

There are further disclosed procedures for preparing the aforesaid noveltetrahydronaphthoquinone as well as procedures for preparing certainisobenzofurans which were not heretofore available.

It should be noted that, while the numbering of the compounds in theflow sheets set forth below is internally sequential, it has been foundconvenient to utilize a separate decade of numbering for each sequence.Hence, certain numbers in certain decades are not utilized. ##STR1##

The isobenzofurans of the present invention are provided by the reactionsequence shown as Sequence A above. In this reaction sequence, R₇ ishydrogen or lower alkyl and R₉ is hydrogen, lower alkyl or lower alkoxy,phenyl- or substituted phenyl-lower alkyl, wherein the prefix "loweralk" signifies a hydrocarbon moiety of 1 to 5 carbon atoms, or halo. Inthe reaction scheme, R₉ ' and R₉ " are differentiated by the "primeindicator" since the prime designated constituent may have any of thevalues shown in the group and may be the same as, or different from, theother member of the group.

In the reaction Sequence A above, the appropriate aminobenzoic acid I isdiazotized to form the unisolated benzyne intermediate II which istrapped with furan to provide the tricyclic Diels-Alder adduct III.Coumalic acid V is heated with copper to provide the pyrone VI which isreacted with the tricyclic adduct III to form the pentacyclicDiels-Alder adduct VII. The pentacyclic adduct VII may then be thermallydissociated to form the desired isobenzofuran VIII. Since theisobenzofuran has a tendency to deteriorate rapidly -- that is to say,by oxidation or polymerization -- the isobenzofuran VIII is not usuallyisolated, but its precursor VII is utilized in the principal reactionsequence wherein it is thermally decomposed in situ.

While the foregoing reaction sequence is known in the literature for thepreparation of isobenzofuran itself (i.e., Compound VIIIa), where R₉ 'as distinguished from R₉ " is lower alkoxy, Compound III is not formedand, thus, the readily available 2-amino-3-methoxybenzoic acid, forexample, cannot be utilized to make the appropriate monomethoxytricyclic adduct III. Since it does not make any difference, in theultimate reaction sequence where a single alkoxy moiety is present in(i.e., the 4- or 7- positions) the benzofuran ring, there is utilized asthe appropriate benzyne precursor, the regioisomer thereof -- namely,the 2-amino-6-alkoxybenzoic acid I.

The precursor for the AB ring system of the anthracycloquinones isprepared in accordance with Scheme B below. It should be noted thatCompounds X through and including the tetralone XIII are knowncompounds.

The tetralone XIII is then ethynylated, suitably with ethynyl magnesiumGrignard, and, the thus produced ethynylcarbinol XIV is hydrated with amercuric alkanoate, suitably mecuric acetate, to provide the tetralin XVwhich, in turn, is oxidized to the bicyclic quinone XVI. This oxidationis suitably carried out with argentic oxide in acetone. Other agents,such as aluminum chloride followed by lead tetraacetate, are operativebut not preferred. ##STR2##

The isobenzofuran VIII (or its immediate precursor VII) is then reactedwith the bicyclic quinone XVI to provide the Diels-Alder adduct XX.Diels-Alder adduct XX is subjected to selective aromatization followedby reductive acylation suitably in the presence of the desired acylanhydride, suitably an alkanoic anhydride, such as acetic anhydride, toprovide the triacylate XXII. Oxidation of the aromatic C ring providesthe quinone XXIII. Where this oxidation is allowed to proceed for toolong a time, a further ketone function would be provided at the C-7position on the A ring.

In the normal reaction sequence, the triacylated quinone XXII ishydrolyzed to provide the known trihydroxy ketone XXIV which, in turn,is hydroxylated at C-7 by methods known to the art to provide the known(±)-4-demethoxydaunomycinone and its corresponding D ring substitutedanalog (XXV). This end product may also be obtained by protection of theside chain ketone suitably by ketalization (to XXVI) followed by overoxidation to the 7-ketone ketal XXVII and reduction, preferably withsodium borohydride, followed by epimerization and acid hydrolysis to thedesired XXV. ##STR3##

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The reaction sequence for the preparation of isobenzofuran itself --that is to say, Compound VIIIa or its immediate precursor which isactually utilized in the process of the present invention -- is carriedout in accordance with the method of Fieser and Haddadin (Can. J. Chem.43 1599 (1965)). This method may be employed as well where R₇ is loweralkyl and where R₉ ' and R₉ " are other than alkoxy. The method is not,however, operative where R₉ ' = R₉ " = alkoxy since, it is believed,that the alkoxy group vicinal to the amino group prevents the formationof the benzyne II due to resonance stabilization.

The method is, however, operative where R₉ ' = hydrogen and R₉ " =alkoxy -- that is to say, the alkoxy group is vicinal to the carboxymoiety -- and this embodiment is used where a mono substitution in the Dring of the tetracyclic quinonoid end products is desired since the sameregioisomers would be produced regardless of whether a single alkoxygroup is present in the 4- or 7-positions of the isobenzofuran moietyVIII.

In the preferred embodiments of the invention, certain combinations ofthe R₇ and R₉ moieties are preferred, especially preferred are thosewhere all R₇ and R₉ groups are hydrogen. Where the R₇ groups are otherthan hydrogen, the R₉ groups are hydrogen and, conversely, where the R₉groups are other than hydrogen, the R₇ groups are hydrogen. Thepreferred products of this invention, thus, are mono or bisubstituted inthe 1- and 4- or 2- and 3-positions of the tetracyclic moietiesprovided, however, that ether groups are present either at the 1- or atthe 4-positions.

The R₇ moieties may be hydrogen, alkyl, suitably lower alkyl of 1-5carbon atoms, in a branch or straight chain -- for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, isopentyl,or the like. They may be phenyl- or substituted phenyl lower alkyl wherethe substituents are lower alkyl, lower alkoxy, or halo where the "loweralk" moiety contains 1-5 carbon atoms in a straight or branch chain.They may also be halogen, suitably chlorine or bromine.

The R₉ moieties have the values of hydrogen, lower alkyl, phenyl loweralkyl and substituted phenyl lower alkyl, as well as lower alkoxy, whenthese moieties are as defined for R₇, as well as halogen as defined inR₇.

R₆ is lower alkanoyl of 1-5 carbon atoms such as formyl, acetyl,propionyl, butyryl, or valeryl or the like, or phenyl lower alkanoylsuch as benzoyl, phenylacetyl, phenylpropionyl, phenylbutyryl, and thelike.

Thus, the appropriate 2-amino-6-alkoxybenzoic acid I is diazotized andcondensed with furan in accordance with the procedures of reactionsequence A and, similarly, subsequently added to alpha pyrone to givethe corresponding isobenzofuran precursor. In the case of the precursorfor the 4-methoxyisobenzofuran, this is VIIb.

As stated hereinabove, Compound XIII is a known compound (Lewis et al J.Am. Chem. Soc. 74 5321 (1952)). This tetralone is then ethynylated toprovide the carbinol XIV. Such ethynylation may be carried out utilizingan alkali metal ethyne such as lithium ethyne or utilizing an ethynylmagnesium halide. It has been found that the use of the latter -- thatis to say, the Grignard reagent -- gives substantially superior results.There is prepared, in the usual manner, a substantial excess, suitablyabout 3 moles per mole of tetralone XIII to be used, of ethynylmagnesium halide, suitably bromide, an ethereal solvent, suitablytetrahydrofuran, dioxan or diethyl ether.

In this procedure, ethyl magnesium bromide is added to a saturatedsolution of acetylene in tetrahydrofuran in an inert atmosphere. Thepassage of acetylene gas is continued and the tetralone XIII in,suitably, tetrahydrofuran is added. After completion of the tetraloneaddition, the passage of acetylene is continued for a short time,suitably for about one hour, and thereafter, the reaction mixture heldat ambient temperature overnight.

The reaction mixture is then quenched, preferably by the addition ofcold saturated ammonium chloride solution, or aqueous oxalic acid, theorganic (ethereal) phase set aside and retained, and the aqueous phaseextracted with a suitably non-hydroxylic, water immiscible, organicsolvent, preferably ethyl acetate. The ethyl acetate extract and theether extract are then combined, dried, and evaporated to dryness toyield the ethynyl carbinol XIV. This residue may be further purified.

The manner of purification is not critical and will depend upon thequantities available. It has been found that chromatography on silica,utilizing as an eluent a mixture of an alkanol with an alkylene halide,suitably 3% methanol in methylene chloride may be employed.

The thus produced ethynyl carbinol(XIV) is then hydrated to form thecorresponding tetralin XV. In this procedure, the ethynyl carbinol XIVis taken up in a reaction inert polar organic solvent, suitably ahalogenated hydrocarbon such as chloroform, methylene chloride or thelike, or in an alkyl alkanoic such as ethyl acetate, the latter beingespecially preferred. There is also prepared a fresh solution ofmercuric ion. The source of mercuric ion is not critical -- salts ofmineral acid such as mercuric sulfate or salts of organic acids such asmercuric acetate or yellow mercuric oxide itself may be employed. It isespecially preferred, however, to utilize mercuric acetate.

In this procedure, a substantial excess, suitably between about 2 toabout 3 moles of mercuric acetate per mole of carbinol XIV are stirredin the above polar solvent at ambient temperature in an inertatmosphere, suitably a nitrogen atmosphere, for about eight to abouteighteen hours. The reaction is then quenched by the addition of gaseoushydrogen sulfide until no further black precipitate is formed. The blackprecipitate (of mercuric sulfide) is removed by filtration reactionmixture and the filtrate worked up in the usual manner to provide thedesired tetralin XV. The

The tetralin XV is then oxidized to the corresponding benzoquinone XVI.The tetralin XV is taken up in a reaction inert, water miscible organicsolvent. In view of the fact that the present step involves oxidation,said solvent should be relatively inert to oxidation. It has been foundthat ketones, suitably dialkyl ketone, preferably acetone, may beutilized. It is further preferred that the solvent be heated to atemperature at or near its boiling point. To the warm solution is addeda substantial excess of the oxidizing agent. It is preferred to utilize2 to 6 moles, suitably about 3 to about 5 moles, of oxidizing agent permole of tetralin XV. It has been found advisable to briefly sonicate themixture to obtain uniform dispersal of the oxidant. Among the oxidizingagents which may be used silver (II) oxide (argentic oxide) isespecially preferred. The reaction is then initiated by the addition ofa small amount of acid, suitably mineral acid, preferably 6N nitricacid. The reaction is rapid and should be considered complete within 3to 10 minutes.

The acid utilized should be a strong acid; however, the quantity thereofis more critical than its nature. The amount of acid utilized should bejust sufficient to dissolve all of the silver oxide. If an amountsubstantially greater than this is employed, the water present in theacid will interfere with the reaction and lower the yields obtained. Thereaction is quenched by the addition of water and the reaction mixtureis then extracted, suitably with a water immiscible reaction organicsolvent, suitably an halogenated hydrocarbon solvent such as chloroform.

The isobenzofuran VIII, or its immediate precursor VII, is thencondensed with the benzoquinone XVI in a Diels-Alder reaction.

As stated heretofore, the isobenzofurans are generally not stable andtend to deteriorate rapidly. On the other hand, they are very readilygenerated in situ from the corresponding pentacyclic lactone VII bythermolysis. In the preferred procedure, the lactone VII is taken up ina reaction inert water and hydrocarbon miscible solvent, especiallysuitably are the ethers of ethylene glycol, most preferably the dialkylethers of diethylene glycol such as, for example, diglyme. In thisprocedure, the bicyclic quinone XVI is taken up in the solvent andheated under an inert atmosphere, suitably a nitrogen atmosphere, forfrom five to ten minutes at a temperature slightly below reflux -- thatis to say, between 130° and 150° C. Thereafter the appropriate lactoneVII is added portion-wise in slight excess, suitably a 10% excess. Thereaction mixture is very briefly heated for a few minutes, cooled toambient temperature, and quenched with water which causes theDiels-Alder adduct to precipitate. The adduct XX is removed byfiltration and dried under reduced pressure.

The C ring, containing the oxa-bridge, is then aromatized to thecorresponding anthraquinone XXI. In this procedure, the Diels-Alderadduct XX is taken up in an anhydrous alkanoic acid, suitably a loweralkanoic acid -- for example, glacial acetic acid -- and heated,suitably under reflux and in an inert atmosphere, suitably a nitrogenatmosphere, in the presence of the appropriate alkali metal alkanoate --for example, where acetic acid is used as a solvent, anhydrous sodiumacetate. It is especially preferred to employ substantially exactly twomoles of the alkanoate per mole of Diels-Alder adduct. The reactionmixture is heated from between about 8 to about 18 hours approximately,cooled to ambient temperature, and quenched with water which causes theappropriate anthraquinone XXI to be precipitated. The precipitate isremoved by filtration and dried under reduced pressure. The compoundmay, if desired, be further purified by chromatography on silica gel.

Such purification, however, is not necessary for the next step in thesynthetic sequence.

The anthraquinone XXI is then subjected to reductive acylation. Thereductive acylation is carried out with a suitable reducing agent in thepresence of an appropriate acyl anhydride. It is preferred to utilize analkanoyl anhydride, suitably a lower alkanoyl anhydride such as aceticanhydride, and the preferred reducing agent is zinc dust.

The reaction mixture is heated, suitably under reflux, for approximately5 to 15 minutes in an inert, suitably a nitrogen, atmosphere. Thereaction mixture is cooled, the excess zinc removed by filtration, thefiltrate quenched with warm water, and the aqueous mixture extractedwith a polar water immiscible solvent, suitably a halogenatedhydrocarbon such as chloroform. The extract is worked up in the usualmanner to yield the naphthacene XXII as a residue which may, if desired,be further purified by chromatography.

The aromatic C ring of the naphthacene XXII is oxidized to thecorresponding quinone. This oxidation proceeds rather readily. In thepreferred procedure, the naphthacene XXII is taken up in acetic acid,suitably 80% acetic acid, and treated with an excess of chromiumtrioxide in a similar solvent. Where it is desired that the reaction notproceed beyond the naphthacenedione XXIII, there should be utilized nomore than 4 equivalents of chromium trioxide per mole of the naphthaceneXXII and that the reaction should not be allowed to proceed underconditions more vigorous than ambient temperature for more than 3 hours.

In the event that more vigorous conditions are employed or a greaterexcess of chromium trioxide is utilized, there will be provided thecorresponding naphthacenetrione having a keto group at the 7 position ofthe A ring. If this product is desired, however, as set out in sequenceC XXVI through XXV, the naphthacene XXII is protected. This protectionis suitably carried out by ketalization using an alkylene glycol,suitably a lower alkylene glycol such as ethylene glycol and a catalyticamount of acid. There may be utilized, as for example, p-toluenesulfonicacid or zinc chloride in anhydrous conditions, without a co-solvent orwith a co-solvent, such as benzene. The reaction mixture is heated atbetween 50° C. and 100° C. for from one to ten hours. Under conditionsof ketalization some loss of the R₆ acyl moiety is to be anticipated. Inthe event that this occurs, as shown by, say, a spectroscopic check ofthe reaction product, this unpurified ketal is reacylated in the usualmanner, suitably by reaction with acetic anhydride in the presence ofsodium acetate, zinc chloride, or pyridine.

Hydrolysis of the naphthacenedione XXIII to remove the alkanoyl moietiesis then carried out, suitably under acid conditions. It is preferred totake up the naphthacenedione triester XXIII in a water miscible, polarorganic solvent, suitably acetic acid or ethanol, which mixture is thenacidified, preferably with an excess of concentrated mineral acid,preferably 6N hydrochloric acid, and the mixture heated for from about 1to about 3 hours at from about 50° to about 80°, suitably from about 65°to about 70° C. The reaction product is then quenched with water andextracted with a water immiscible polar solvent, suitably an halogenatedhydrocarbon solvent such as chloroform, which is then worked up in theusual manner to give the known trihydroxy naphthacenedione XXIV.

This trihydroxy compound may then be converted to the corresponding7-hydroxy compound by methods disclosed, say, in U.S. Pat. No.4,021,457.

Where it is desired to proceed with the ketal XXVI, treatment with asubstantial excess -- i.e., 4 to 8 equivalents of chromium trioxide permole of naphthacene -- yields the 7-ketoketal XXVII which is thenreduced with sodium borohydride to yield the 7-hydroxy ketal XVIII. Itshould be noted that such reduction will yield the compound having the7-hydroxy group in a cis orientational relationship with the 9-acyloxygroup as well as in trans orientation therewith.

This stereo isomeric mixture is converted to the desired cis orientationby reaction with trifluoroacetic acid for about 2 hours in accordancewith the procedures of U.S. Pat. No. 4,021,457. The reaction product isnot isolated, but subjected to acid hydrolysis to yield the desiredtetrahydroxynaphthacenedione XXV.

In the following Examples, the units of nmr data are δ; of infra-red areμ; and ultraviolet are nm.

EXAMPLE I 1,4-DIHYDRONAPHTHALENE-1,4-ENDO-OXIDE (IIIa)

Solutions of 20 ml of isoamyl nitrite in glyme (20 ml) and of 13.7 g ofanthranilic acid in glyme (45 ml) were added simultaneously by drops toa refluxing mixture of glyme (50 ml) and furna (50 ml). Refluxing wascontinued for ten minutes and the brown solution was cooled, made basicwith aqueous sodium hydroxide (1N), and extracted with petroleum ether.The extract was washed thoroughly with water, clarified with Norit®,dried, and evaporated to give an oil. The oil solidified on cooling togive 7 g (51% yield) of light yellow solid. Recrystalization of theyellow solid from petroleum ether gave colorless crystalline solid of1,4-dihydronaphthalene1,4-endo-oxide (IIIa), m.p. 53°-54° C. (lit. m. p.56° C.).

nmr: (CDCl₃ ; 60 MHz) 7.25-6.75 (m, 6H), 5.62 (s, 2H),

ir: (KBr) 7.02; 7.53; 7.93

ms: m/e⁺ 144 (M⁺ ; 28.0%), 128 (33.0%), 118 (30.0%), 116 (81.0%), 115(100%), 89 (18.0%).

EXAMPLE II1,4-CARBONYLOXY-9,10-OXIDO-1,4,9,9a,10,10a-HEXAHYDROANTHRACENE (VIIa)

1,4-Dihydronaphthalene-1,4-endo-oxide (IIIa) was dissolved in α-pyrone(2 g) and the solution left to stand at room temperature under nitrogenfor four days, during which time the adduct crystallized. Thecrystalline mass was broken up, filtered and washed with cold methanolto give 4.2 g (87.5% yield) of 1,4-carbonyloxy-9,10-oxido-1,4,9,9a,10,10a-hexahydroanthracene (VIIa), m.p. 105°-107° C. (lit. m.p.105°-107° C.)

nmr: (CDCl₃ ; 100 MHz) 7.16 (s, broad, 4H), 6.48 (t, 2H), 5.28 (m, 1H),5.04 (d, 2H), 3.70 (m, 1H), 2.70 (q, 1H), 2.25 (q, 1H).

ir: (KBr) 5.72

EXAMPLE III 5-METHOXY-1,4-DIHYDRONAPHTHALENE-1,4-ENDO-OXIDE (IIIb)

Solutions of 3.2 ml of isoamyl nitrite in glyme (6.8 ml) and of 3.2 g of2-amino-6-methoxybenzoic acid (Ib) in glyme (6 ml) were addedsimultaneously by drops to a refluxing mixture of glyme (10 ml) andfuran (15 ml). Refluxing was continued for 20 minutes and the reactionmixture cooled. The solution was made basic with aqueous sodiumhydroxide (1N), and extracted with hexane. The extract was washedthoroughly with water, dried, and evaporated to give an off-white solid.Recrystalization of the solid from hexane gave 1.59 g (45% yield) of5-methoxy-1,4-dihydronaphthalene-1,4-endo-oxide (IIIb), m.p. 58°-60° C.

nmr: (CDCl₃ ; 100 MHz) 7.01-6.48 (m, 4H), 5.92 (s, 1H), 5.65 (s, 1H),3.80 (s, 3H).

ir: (KBr) 6.20; 6.78

ms: m/e⁺ 174 (M⁺ ; 27.0%), 159 (14.1%), 148 (34.1%), 146 (100%), 131(52.9%), 115 (82.4%), 103 (51.8%).

Analysis: Calculated for C₁₁ H₁₀ O₂ : C, 75.86; H, 5.75. Found: C,75.40; H, 5.74.

In accordance with the above procedure but where, in place of2-amino-6-methoxybenzoic acid, there is used 2-amino-6-butoxybenzoicacid, 2-amino-6-methylbenzoic acid, 2-amino-6-chlorobenzoic acid,2-amino-6-bromobenzoic acid, 2-amino-6-benzylbenzoic acid,2-amino-6-chlorobenzylbenzoic acid, 2-amino-3,6-diethylbenzoic acid,2-amino-3,6-dichlorobenzoic acid, 2-amino-3,6-dibenzylbenzoic acid,2-amino-4-butylbenzoic acid, 2-amino-4-methylbenzoic acid,2-amino-4-chlorobenzoic acid, 2-amino-4,5-diethylbenzoic acid,2-amino-4,5-dibromobenzoic acid, 2-amino-4,5-dibenzylbenzoic acid, thereis obtained the corresponding5-butoxy-1,4-dihydronaphthalene-1,4-endo-oxide,5-methyl-1,4-dihydronaphthalene-1,4-endo-oxide,5-chloro-1,4-dihydronaphthalene-1,4-endo-oxide,5-bromo-1,4-dihydronaphthalene-1,4-endo-oxide,5-benzyl-1,4-dihydronaphthalene-1,4-endo-oxide,5-chlorobenzyl-1,4-dihydronaphthalene-1,4-endo-oxide,5,8-diethyl-1,4-dihydronaphthalene-1,4-endo-oxide,5,8-dichloro-1,4-dihydronaphthalene-1,4-endo-oxide,5,8-dibenzyl-1,4-dihydronaphthalene-1,4-endo-oxide,6-butyl-1,4-dihydronaphthalene-1,4-endo-oxide,6-methyl-1,4-dihydronaphthalene-1,4-endooxide,6-chloro-1,4-dihydronaphthalene-1,4-endo-oxide,6,7-diethyl-1,4-dihydronaphthalene-1,4-endo-oxide,6,7-dibromo-1,4-dihydronaphthalene-1,4-endo-oxide,6,7-dibenzyl-1,4-dihydronaphthalene-1,4-endo-oxide.

EXAMPLE IV 1,4-CARBONYLOXY-9,10-OXIDO-5- and8-METHOXY-1,4,9,9a,10,10a-HEXAHYDROANTHRACENE (VIIb)

5-Methoxy-1,4-dihydronaphthalene-1,4-endo-oxide (IIIb) (1.05 g) wasdissolved in α-pyrone (VI) (0.578 g) with slight warming and theresulting mixture left to stand at room temperature under nitrogen forten days. Ether was added and solid filtered off to give 1.35 g (83%yield of 1,4-carbonyloxy-9,10-oxido-5- and8-methoxy-1,4,9,9a,10,10a-hexahydroanthracene (VIIb). The product can bepurified by chromatography using florisil column eluted with 25% etherin hexane. m.p. 120° C. (decomp.)

nmr: (CDCl₃ ; 60 MHz) 7.38-6.50 (m, 5H), 5.35 (m, 2H), 5.13 (m, 1H),3.83 (s, 3H), 3.83 (m, 1H), 2.75 (m, 1H), 2.32 (m, 1H).

ir: (KBr) 5.73

Analysis: Calculated for C₁₆ H₁₄ O₄ : C, 71.11; H, 5.19. Found: C,70.93; H, 5.84.

In accordance with the above procedure but where, in place of5-methoxy-1,4-dihydronaphthalene-1,4-endo-oxide, there is employed5-butoxy-1,4-dihydronaphthalene-1,4-endooxide,5-methyl-1,4-dihydronaphthalene-1,4-endo-oxide,5-chloro-1,4-dihydronaphthalene-1,4-endo-oxide,5-bromo-1,4-dihydronaphthalene-1,4-endo-oxide,5-benzyl-1,4-dihydronaphthalene-1,4-endo-oxide,5-chlorobenzyl-1,4-dihydronaphthalene-1,4-endo-oxide,5,8-diethyl-1,4-dihydronaphthalene-1,4-endo-oxide,5,8-dichloro-1,4-dihydronaphthalene-1,4-endo-oxide,5,8-dibenzyl-1,4-dihydronaphthalene-1,4-endo-oxide,6-butyl-1,4-dihydronaphthalene-1,4-endo-oxide,6-methyl-1,4-dihydronaphthalene-1,4-endo-oxide,6-chloro-1,4-dihydronaphthalene-1,4-endo-oxide,6,7-diethyl-1,4-dihydronaphthalene-1,4-endo-oxide,6,7-dibromo-1,4-dihydronaphthalene-1,4-endo-oxide,6,7-dibenzyl-1,4-dihydronaphthalene-1,4-endo-oxide, there is obtainedthe corresponding 1,4-carbonyloxy-9,10-oxido-5- and8-butoxy-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-5- and8-methyl-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-5- and8-chloro-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-5- and8-bromo-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-5- and8-benzyl-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-5- and8-chlorobenzyl-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-5,8-diethyl-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-5,8-dichloro-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-5,8-dibenzyl-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-6- and7-butyl-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-6- and7-methyl-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-6- and7-chloro-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-6,7-diethyl-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-6,7-dibromo-1,4,9,9a,10,10a-hexahydroanthracene,1,4-carbonyloxy-9,10-oxido-6,7-dibenzyl-1,4,9,9a,10,10a-dihydroanthracene.

EXAMPLE V 5,8-DIHYDRO-1,4-DIMETHOXY-6-ETHOXYNAPHTHALENE (XII)

To a suspension of 4a,5,8,8a-tetrahydro-6-ethoxy-1,4-naphthoquinone (XI)(6.6 g, 32 mmole) in 18 ml of absolute ethanol was added with stirringunder N a solution of sodium ethoxide prepared from dissolving 22 gsodium in 45 ml absolute ethanol under nitrogen. The mixture was heatedto reflux for 10 minutes and cooled under N₂ to room temperature. Methyliodide (14.5 g) was added dropwise to the solution. After addition, thereaction mixture was heated to reflux for one hour and cooled to roomtemperature. Further cooling in ice bath resulted in a tan coloredprecipitate. The precipitate was separated by filtration andrecrystalized from ethanol to give 5.87 g (78.5% yield) of5,8-dihydro-1,4-dimethoxy-6-ethoxynaphthalene (XII), m.p. 102°-103° C.

nmr: (CDCl₃ ; 100 MHz) 6.63 (s, 2H), 4.76 (m, 1H), 3.80 (q, 2H), 3.76(s, 6H), 3.31 (m, 4H), 1.28 (t, 3H)

ir: (KBr) no carbonyl absorption

ms: m/e⁺ 234 (M⁺ ; 100%), 219 (6%), 205 (20%), 203 (55%), 189 (51%).

EXAMPLE VI 1,4-DIMETHOXY-6-TETRALONE (XIII)

5,8-Dihydro-1,4-dimethoxy-6-ethoxynaphthalene (XII) (3.5 g, 15 mmole)was dissolved in 88 ml hot ethanol and then cooled to room temperature.The suspension was stirred with hydrochloric acid (2N) (17.5 ml) forfifteen minutes. The reaction mixture was poured onto ice water andfiltered to give as a tan solid 1,4-dimethoxy-6-tetralone (XIII) (2.67g, 86.5% yield). m.p. 99°-100° C. (ethanol).

nmr: (CDCl₃) 6.68 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.48 (s, 2H),3.04 (t, 2H), 2.50 (t, 2H).

ir: (KBr) 5.89

ms: m/e⁺ 206 (M⁺ ; 100%), 191 (11.1%), 178 (3.6%), 164 (65.1%).

EXAMPLE VII 1,4-DIMETHOXY-6-ETHYNYL-6-HYDROXY-5,8-DIHYDRO-(7H)NAPHTHALENE (XIV)

Acetylene, purified by passing it first through a dry ice acetone trap,then through concentrated sulfuric acid, was bubbled rapidly throughfreshly distilled tetrahydrofuran (20 ml) under nitrogen for one hour.Ethylmagnesium bromide (50 ml, 3.15 M in ether, 15.8 mmole) was addedslowly. The temperature was maintained between 28°-33° C. by coolingwith a water bath. After the complete addition of ethylmagnesiumbromide, the passage of the acetylene gas was continued and1,4-dimethoxy-6-tetralone (XIII) (1.03 g, 5 mmole) in drytetrahydrofuran (5,0 ml) was added with stirring. After addition, thepassage of the acetylene was continued for an extra one hour and thereaction mixture was left stirring at room temperature overnight. Thereaction mixture was quenched with saturated oxalic acid and extractedwith chloroform. The chloroform extract was washed well with water,dried over anhydrous magnesium sulfate, and evaporated to dryness. Theoil residue was triturated with ether to give1,4-dimethoxy-6-ethynyl-6-hydroxy-5,8-dihydro-(7H)naphthalene (XIV) as awhite solid, m.p. 103°-105° C. (ethanol).

nmr: (CDCl₃ ; 100 MHz) 6.62 (s, 2H), 3.78 (s, 6H), 2.95 (m, 4H), 2.40(s, 1H), 2.16 (s, 1H), 2.02 (t, 2H)

ir: (KBr) 2.75; 3.02

ms: m/e⁺ 232 (M⁺ ; 100%), 214 (18.8%), 199 (7.4%), 175 (12.8%), 164(43.7%).

EXAMPLE VIII 1,4-DIMETHOXY-6-ACETOXY-6-ACETYL-5,8-DIHYDRO-(7H)NAPHTHALENE (XV)

A mixture of1,4-dimethoxy-6-ethynyl-6-hydroxy5,8-dihydro-(7H)naphthalene (XIV) (2.0g, 8.65 mmole) and mercuric acetate (15.85 g, 18.3 mmole) in ethylacetate (850 ml) was stirred at room temperature under nitrogenovernight. Hydrogen sulfide was bubbled through until no more blackprecipitate was formed. The black precipitate was removed by filteringthrough a celite pad. The filtrate was washed with saturated sodiumbicarbonate and water, and dried over anhydrous magnesium sulfate.Removal of solvent under reduced pressure gave1,4-dimethoxy-6-acetoxy-6-acetyl-5,8-dihydro-(7H) naphthalene (XV) as anoff-white solid (2.57 g). Recrystalization from ethanol gave1,4-dimethoxy-6-acetoxy-6-acetyl-5,8-dihydro-(7H)naphthalene (2.4 g, 96%yield), m.p. 120°-122° C.

nmr: (CDCl₃ ; 100 MHz) 6.63 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H,3.06-2.00 (m, 6H), 2.20 (s, 3H), 2.02 (s, 3H)

ir: (KBr) 5.79; 5.83

ms: m/e⁺ 292 (M⁺ ; 20.4%), 250 (1.9%), 232 (100%), 217 (25.8%), 207(29.2%), 201 (38.1%), 189 (61.9%), 43 (84.7%).

Analysis: Calculated for C₁₆ H₂₀ O₅ : C, 65.75; H, 6.85. Found: C,65.90; H, 6.72

In accordance with the above procedure but where, in place of mercuricacetate, there is utilized mercuric formate, propionate or butyrate,there is obtained the corresponding 6-formyloxy, 6-propionoxy or6-butyroxy-6-acetyl-1,4-dimethoxy-5,8-dihydro-(7H)naphthalene.

EXAMPLE IX 5,8-DIHYDRO-6-ACETYL-6-ACETOXY-1,4-(7H)NAPHTHAQUINONE (XVI)

To a solution of1,4-dimethoxy-6-acetoxy-6-acetyl-5,8-dihydro-(7H)naphthalene (XV) (0.368g) in dioxane (20 ml) was added argentic oxide (4 eq). The mixture wassonicated briefly to achieve an even dispersal of oxidant. The resultingsolution was stirred vigorously with a magnetic stirrer and nitric acid(6N, 1.5 ml) was added in one portion. Stirring was continued until allthe silver oxide was consumed (three to five minutes). The reactionmixture was diluted with water and extracted with chloroform. Thechloroform extract was washed well with water, dried, and evaporated todryness. The oil residue was tritrated with ethanol and petroleum etherto give a light yellow solid (0.312 g, 94.5% yield). Recrystalizationfrom ethanol/petroleum ether gave5,8-dihydro-6-acetyl-6-acetoxy-1,4-(7H)naphthaquinone (XVI) as brightyellow crystals, m.p. 86°-87° C.

nmr: (CDCl₃ ; 100 MHz) 6.74 (s, 2H), 2.90 (m, 2H), 2.50 (m, 2H), 2.20(m, 2H), 2.18 (s, 3H), 2.08 (s, 3H)

ir: (KBr) 5.82; 6.05; 6.24

ms: m/e⁺ 263 (M⁺ +1; 1%) 219 (23.2%), 202 (17.3%), 187 (3%), 178 (4.2%),160 (8.5%), 43 (100%).

In accordance with the above procedure but where, in place of1,4-dimethoxy-6-acetoxy-6-acetyl-5,8-dihydro-(7H) naphthalene, there isused any of the corresponding1,4-dimethoxy-6-alkanoyloxy-6-acetyl-5,8-dihydronaphthalenes produced inExample VIII, there is obtained the corresponding5,8-dihydro-6-acetyl-6-alkanoyl-1,4-(7H)naphthaquinone (XVI).

EXAMPLE X5,5a,7,10,11a,12-HEXAHYDRO-9-ACETYL-9-ACETOXY-5,12-OXIDO-6,11-(8H)NAPHTHACENEQUINONE(XXa)(Anthracycline Numbering)

5,8-Dihydro-6-acetyl-6-acetoxy-1,4-(7H) naphthoquinone (XVI) (0.262 g, 1mmole) was dissolved in diglyme (10 ml) and heated at 140° C. undernitrogen for five minutes while the pentacyclic lactone (VIIa) (0.264 g,1.1 mmole) was added in portions. After addition, the mixture was heatedfor two extra minutes, cooled to room temperature, and precipitated withwater. The precipitate was filtered, washed well with water, and driedunder reduced pressure to give5,5a,7,10,11a,12-hexahydro-9-acetonyl-9-acetyl-5,12-oxido-6,11-(8H)naphthacenequinone(XXa) (0.365 g, 96% yield).

nmr: (CDCl₃ ; 100 MHz) 7.14 (m, 4H), 5.75 (m, 2H), 3.60 (m, 2H),3.00-1.88 (m, 6H), 2.06 (s, 3H), 1.95 (s, 3H)

ir: (CHCl₃) 5.77; 5.82; 6.00

ms: m/e⁺ 380 (M⁺ ; 0.2%) 337 (1.4%), 321 (0.3%), 295 (5.7%), 277 (1.4%),118 (100%), 43 (60.7%).

In accordance with the above procedure but where, in place of5,8-dihydro-6-acetyl-6-acetoxy-1,4-(7H)naphthoquinone, there is employedany one of the other 5,8-dihydro6-acetyl-6-alkanoyloxy-1,4-(7H)naphthoquinones (XVI) produced in Example (IX), there is obtained thecorresponding5,5a,6,10,11a,12-hexahydro-9-acetyl-9-alkanoyloxy-5,12-oxido-6,11-(8H)naphthacenequinone(XXa).

EXAMPLE XI 5,5a,7,10,11a,12-HEXAHYDRO-9-ACETYL-9-ACETOXY-4-METHOXY (AND1-METHOXY)-5,12-OXIDO-6,11-(8H)NAPHTHACENEQUINONE (XXb)

Diglyme was warmed in an oil bath under nitrogen at 145° C.5,8-Dihydro-6-acetyl-6-aceoxy-1,4-(7H)naphthoquinone (XVI) was added andheated for five minutes (640 mgs) and pentacyclic lactone (VIIb) wasadded (660 mgs) in small portions while backflushing with nitrogen.After addition, the solution was stirred at 145° C. for five moreminutes. The mixture was cooled to room temperature and poured intowater. The cloudy water layer was extracted with ethyl acetate. Theorganic layer was washed three times with water and then with saturatedsaline. Concentration, followed by addition of water, gave an offwhiteoily solid which was washed several times with water and pumped dry.

nmr: Showed a very complex mixture of regioisomers

ir: (CHCl₃) 5.79; 6.02

The mixture was directly aromatized as in Example XIII.

The foregoing procedure may be carried out with any of the otherpentacyclic lactones produced in accordance with Example IV to providethe corresponding 1-butoxy-(and 4-butoxy)-; 1-methyl-(and 4-methyl)-;1-chloro-(and 4-chloro)-; 1-bromo-(and 4-bromo)-; 1-benzyl-(and4-benzyl)-; 1-chlorobenzyl-(and 4-chlorobenzyl)-; 1,4-diethyl;1,4-dichloro; 1,4-dibenzyl; 2-butyl-(and 3-butyl)-; 2-methyl-(and3-methyl)-; 2-chloro-(and 3-chloro)-; 2,3-dimethyl-; 2,3-dibromo-; and2,3-dibenzyl-9-acetyl-9-acetoxy-5,12-oxido-5,5a,7,10,11a,12-hexahydro-6,11-(8H)naphthacenequinones (XX) which aresimilarly aromatized as in Example XIII.

EXAMPLE XII 7,10-DIHYDRO-9-ACETOXY-9-ACETYL-6,11-(8H) NAPHTHACENEQUINONE(XXIa)

A mixture of5,5a,7,10,11a,12-hexahydro-9-acetyl-9-acetoxy-5,12-oxido-6,11-(8H)naphthacenequinone(XXa) (0.360 g, 0.95 mmole) and anhydrous sodium acetate (0.155 g, 1.9mmole) in acetic acid (10 ml) was heated at reflux under nitrogen forsixteen hours, and cooled to room temperature. The mixture wasprecipitated with water. The precipitate was washed well with water,dried under reduced pressure to give a yellowish solid. Chromatographyon silica gel gave the yellow solid identified as7,10-dihydro-9-acetyl-6,11-(8H)naphthacenequinone (XXIa), (0.2312g, 67%yield), m.p. 254°-256° C. (from acetic acid)

nmr: (CDCl₃ ; 100 MHz) 8.70 (s, 2H), 8.12 (m, 2H), 7.74 (m, 2H), 3.14(m, 2H), 3.0-2.0 (m, 4H), 2.25 (s, 3H), 2.11 (s, 3H)

ir: (CDCl₃) 5.77; 5.82; 6.01

ms: m/e⁺ 362 (M⁺ ; 1.9%), 320 (5%), 302 (49.6%), 277 (100%), 259(19.2%), 249 (17.3%), 118 (77.7%), 43 (62.5%).

EXAMPLE XIII 7,10-DIHYDRO-9-ACETOXY-9-ACETYL-4-METHOXY(AND1-METHOXY)-6,11-(8H)NAPHTHACENEQUINONE (XXIb) (REGIOISOMERIC MIXTURE)

The product of Example XI was dissolved in acetic acid (25 ml) withsodium acetate (anh.) (410 mgs). The reaction mixture was placed undernitrogen and refluxed for five hours. The mixture was then cooled andpoured into water. The aqueous phase was extracted three times withchloroform. The organic layer was washed several times with water andonce with saturated saline. Concentration and chromatography on silicagel (5:1 chloroform/ethyl acetate) gave 540 mgs of orange solid as7,10-dihydro-9-acetoxy-9-acetyl-4-methoxy(and1-methoxy)-6,11-(8H)naphthacenequinone (XXIb) (regioisomeric mixture),(57% from VIIb, m.p. 221°-223° C.) (sealed tube, decomp.).

nmr: (CDCl₃ ; 100 MHz) 9.11 (s, 1H), 8.58 (s, 1H), 7.64 (m, 2H), 7.04(m, 1H), 4.03 (s, 3H), 3.3 to 2.1 (m, 6H), 2.16 (s, 3H), 2.08 (s, 3H)

ir: (CHCl₃) 5.78; 5.99; 6.15

uv (abs. EtOH) 246; 440 nm

ms: m/e⁺ 392 (M⁺), 346, 332, 330, 307

In accordance with the above procedure, but starting with any of theproducts of Example XI, there is obtained the corresponding1-butoxy-(and 4-butoxy)-; 1-methyl-(and 4-methyl)-; 1-chloro-(and4-chloro)-; 1-bromo-(and 4-bromo)-; 1-benzyl-(and 4-benzyl)-;1-chlorobenzyl-(and 4-chlorobenzyl)-; 1,4-diethyl-; 1,4-dichloro-;1,4-dibenzyl-; 2-butyl-(and 3-butyl)-; 2-methyl-(and 3-methyl)-;2-chloro-; (and 3-chloro)-; 2,3-dimethyl-; 2,3-dibromo-; and2,3-dibenzyl-9-acetyl-9-acetoxy-7,10-dihydro-6,11-(8H)naphthacenequinones (XXI).

EXAMPLE XIV7,10-DIHYDRO-9-ACETYL-6,9,11-TRIHYDROXY-(8H)NAPHTHACENE-6,9,11-TRIACETATE(XXIIa)

A suspension of 7,10-dihydro-9-acetoxy-9-acetyl-6,11-(8H)naphthacenequinone (XXIa) (9.5 mg) and excess zinc dust in aceticanhydride (1 ml) was heated at 110° C. under nitrogen for 20 minutes.Yellow color disappeared during the reaction. The zinc dust was removedby filtering the reaction mixture through a celite pad. The excessacetic anhydride was hydrolyzed with warm water. The resulting solutionwas extracted with chloroform and the chloroform extract washed wellwith water, then dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure to give an oily residue. The residue waschromatographed with silica prep plates eluting with 1%methanol/chloroform to give a light colored oil which solidified bytriturating with chloroform and hexane. The solid was collected andidentified as7,10-dihydro-9-acetyl-6,9,11-trihydroxy-(8H)naphthacene-6,9,11-triacetate(XXIIa) (10.9 mg, 92.4% yield).

nmr: (CDCl₃ ; 100 MHz) 8.28 (s, 2H), 7.95 (m, 2H), 7.47 (m, 2H), 3.29(m, 2H), 2.88 (m, 2H), 2.75-2.00 (m, 2H), 2.57 (s, 6H), 2.23 (s, 3H),2.00 (s, 3H)

ir: (CDCl₃) 5.66; 5.72; 5.80

ms: m/e⁺ 448 (M⁺ ; 12.1%), 406 (22.6%), 388 (3.0%), 364 (14.0%), 346(28.1%), 320 (2.33%), 304 (100%), 278 (14.4%), 263 (21.5%), 262 (21 2%),32 (29.8%)

In accordance with the above procedure but where, in place of aceticanhydride, there is utilized an alkanoic anhydride of the grouppropionic anhydride, butyric anhydride or valaric anhydride, there isobtained the corresponding7,10-dihydro-9-acetyl-1,6,9,11-trihydroxy-(8H)naphthacene-6,11-dialkanoate-9-acetate(XXII).

EXAMPLE XV 7,10-DIHYDRO-9-ACETYL-6,9,11-TRIHYDROXY-4-METHOXY(AND1-METHOXY)-(8H)NAPHTHACENE-6,9,11-TRIACETATE (XXIIb) (REGIOISOMERICMIXTURE)

The product of Example XIII, the quinone (XXIb) (230 mg) was heated withzinc dust in acetic anhydride under nitrogen at 110° C. for about 20minutes. Color changed from red to yellow. The reaction mixture wasfiltered through celite, and the filtrate diluted with hot water, andthen cooled and extracted three times with chloroform. The organic layerwas then washed thoroughly with water and once with saturated saline.The filtrate was dried briefly over anhydrous sodium sulfate,concentrated, and chromatographed on silica gel. Elution withchloroform/methanol gave 180 mgs (70% yield) of unstable7,10-dihydro-9-acetyl-6,9,11-trihydroxy-4-methoxy(and1-methoxy)-(8H)naphthacene-6,9,11-triacetate (XXIIb), regioisomericmixture, as a yellow oil which was stored at 0° C.

nmr: (CDCl₃ ; 100 MHz) 8.80 (s, 1H), 8.30 (s, 1H), 7.51 (m, 2H), 6.78(t, 1H), 4.08 (s, 3H), 3.3 to 2.1 (m, 6H), 2.59 (s, 6H), 2.25 (s, 3H),2.02 (s, 3H)

ir: (CHCl₃) 5.70; 5.78

ms: m/e⁺ 478 (M⁺), 436, 418, 394, 376, 334

uv (abs. EtOH) 222, 264, 378, 400 nm

The foregoing procedure may be carried out with any of the othernaphthacenequinones produced in accordance with Example XIII to providethe corresponding 1-butoxy-(and 4-butoxy)-; 1-methyl-(and 4-methyl)-;1-chloro-(and 4-chloro)-; 1-bromo-(and 4-bromo)-; 1-benzyl-(and4-benzyl)-; 1-chlorobenzyl-(and 4-chlorobenzyl)-; 1,4-diethyl-;1,4-dichloro-; 1,4-dibenzyl-; 2-butyl-(and 3-butyl)-; 2-methyl-(and3-methyl)-; 2-chloro-(and 3-chloro)-; 2,3-dimethyl-; 2,3-dibromo-; and2,3-dibenzyl-9-acetyl-6,9,11-trihydroxy-7,10-dihydro-(8H)naphthacene-6,9,11-triacetates(XXII).

EXAMPLE XVI (+)-4-DEMETHOXY-7-DEOXYDAUNOMYCINONE-6,9,11-TRIACETATE(XXIIIa)

A mixture of chromium trioxide (7 mg) in 80% acetic acid (0.5 ml) wasadded to a solution of7,10-dihydro-6,9,11-trihydroxy-9-acetyl-(8H)naphthacene-6,9,11-triacetate(XXIIa) (7.2 mg) in acetic acid (1 ml) at room temperature undernitrogen. After addition, the solution was stirred for 2 hours anddiluted with water. The resulting mixture was then extracted withchloroform. The chloroform extract was washed well with water and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure to give an oily residue. The residue was chromatographed onsilica gel (chloroform/1% methanol) to give a light colored oil whichsolidified on triturating with chloroform and hexane. The solid wascollected and identified as(+)-4-demethoxy-7-deoxydaunomycinone-6,9,11-triacetate (XXIIIa) (5.3 mg,64% yield). mp 247°-248° C. (EtOAc -- CCl₄)

nmr: (CDCl₃ ; 100 MHz) 8.16 (m, 2H), 7.74 (m, 2H), 3.24 (m, 2H), 2.91(m, 2H), 2.64-2.32 (m, 2H), 2.53 (s, 6H), 2.23 (s, 3H), 2.04 (s, 3H)

ir: (CDCl₃) 5.65; 5.75; 5.80; 5.97

ms: m/e⁺ 478 (M⁺ ; 0.1%), 436 (1.4%), 418 (0.4%), 394 (11%), 376 (9.4%),351 (2%), 334 (100%), 316 (11.2%), 309 (19%), 301 (6.8%), 291 (22.5%),43 (60%)

EXAMPLE XVII (+)-7-DEOXYDAUNOMYCINONE-6,9,11-TRIACETATE(AND THE1-METHOXY REGIOISOMER THEREOF) (XXIIb)

7,10-Dihydro-9-acetyl-4-methoxy(and1-methoxy)-6,9,11-trihydroxy-(8H)naphthacene-6,9,11-triacetate (XXIIb)(110 mgs) was dissolved in acetic acid (15 ml), cooled in a water bath,and placed under nitrogen. Chromium trioxide (110 mgs) in 80% aceticacid (15 ml) was added slowly dropwise. The mixture was stirred at roomtemperature. After two hours, it was poured into water and the water wasextracted three times with chloroform and once with ethyl acetate. Thecombined organic phase was washed with water five times, once withsaturated saline, and dried briefly over sodium sulfate. Concentrationand chromatography on silica gel (5:1 chloroform/methanol) gave7-deoxydaunomycinone-6,9,11-triacetate (and the 1-methoxy regioisomerthereof) (XXIIIb) (11 mg, 10%) as a yellow oil.

nmr: (CDCl₃ ; 100 MHz) 7.7 to 6.9 (m, 3H), 3.90 (s, 3H), 3.2 to 2.2 (m,6H), 2.41 (s, 6H), 2.17 (s, 3H), 1.98 (s, 3H)

ir: (CHCl₃) 5.70, 5.78, 6.01

ms: m/e⁺ 424 (loss of 2 ketene) 364 (loss of 2 ketene + HOAc) (348)(346) (321) (231)

uv (Abs EtOH) 258, 380

The foregoing procedure may be carried out with any of the otherdihydronaphthacenetriacetates produced in accordance with Example XV toprovide the corresponding 1-butoxy-(and 4-butoxy)-; 1-methyl-(and4-methyl)-; 1-chloro-(and 4-chloro)-; 1-bromo-(and 4-bromo)-; 1-benzyl-and 4-benzyl)-; 1-chlorobenzyl-(and 4-chlorobenzyl)-; 1,4-diethyl-;1,4-dichloro-; 1,4-dibenzyl-; 2-butyl-(and 3-butyl)-; 2-methyl-(and3-methyl)-; 2-chloro-(and 3-chloro)-; 2,3-dimethyl-; 2,3-dibromo-; and2,3-dibenzyl-7-deoxy-4-demethoxydaunomycinone-6,9,11-triacetate (XXIII).

EXAMPLE XVIII (+)-4-DEMETHOXY-7-DEOXYDAUNOMYCINONE (XXIVa)

(+)-4-Demethoxy-7-deoxydaunomycinone-6,9,11-triacetate (XXIIIa) (12 mg)was dissolved in acetic acid (5 ml) and mixed with 6N hydrochloric acid(5 ml) at 65°-75° C. under nitrogen. The resulting mixture was heated at75° C. for 2 hours, cooled to room temperature, and diluted with water.Thie solution was extracted with chloroform. The chloroform extract waswashed well with water and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to give(+)-4-demethoxy-7-deoxydaunomycinone (XXIVa) as a red solid (8.78 mg,100% yield).

nmr: (CDCl₃) 13.54 (s, 2H), 8.36 (m, 2H), 7.84 (m, 2H), 3.71 (s, broad,1H), 2.99 (m, 4H), 2.40 (s, 3H), 1.96 (m, 2H)

ir: (KBr) 5.88; 6.17; 6.31

ms: m/e⁺ 352 (M⁺, 17.3%), 334 (18.3%), 309 (100%), 291 (24.7%)

The (+)-4-Demethoxy-7-deoxydaunomycinone (XXIVa) from the above reactionwas identical in all respects with The same substance independentlyprepared in U.S. Pat. No. 4,021,457.

EXAMPLE XIX (+)7-DEOXYDAUNOMYCINONE (AND ITS 1-METHOXY REGIOISOMER)(XXIVb)

7-deoxydaunomycinone-6,9,11-triacetate (and its 1-methoxy regioisomer)(XXIIIb) (7 mgs) was heated in acetic acid (1 ml) and 6N hydrochloricacid (1 ml) at 75° C., under nitrogen, for 2 hours. The resulting redsolution was poured into water and extracted with chloroform. Thechloroform layer was washed repeatedly with water and then once withsaturated saline, and then dried briefly over sodium sulfate.Concentration and chromatography on silica gel (5:1 chloroform ethylacetate) gave racemic 7-deoxydaunomycinone (5.8 mgs, 94% yield) as anorange solid identical in all respects to a sample of racemic7-deoxydaunomycinone previously prepared by an independent route. (J.Am. Chem. Soc., 98 1967 (1967)).

The foregoing procedure may be carried out with any of the other4-demethoxy-7-deoxydaunomycinone triacetates (XXIII) produced inaccordance with Example XVII to provide the corresponding 1-butoxy-(and4-butoxy)-; 1-methyl-(and 4-methyl)-; 1-chloro-(and 4-chloro)-;1-bromo-(and 4-bromo)-; 1-benzyl-(and 4-benzyl)-; 1-chlorobenzyl-(and4-chlorobenzyl)-; 1,4-diethyl-; 1,4-dichloro-; 1,4-dibenzyl-;2-butyl-(and 3-butyl)-; 2-methyl-(and 3-methyl)-; 2-chloro- and3-chloro)-; 2,3-dimethyl-; 2,3-dibromo-; and2,3-dibenzyl-4-demethoxy-7-deoxydaunomycinones (XXIV).

EXAMPLE XX 13-ETHYLENEDIOXY KETAL OF9,10-DIHYDRO-9-ACETYL-6,9,11-TRIHYDROXY-(8H)NAPHTHACENE-6,9,11-TRIACETATE(XXVIa)

9,10-Dihydro-9-acetyl-6,9,11-trihydroxy-(8H)naphthacene-6,9,11-triacetate (0.024 mmole) is taken up in benzene (10ml), ethylene glycol (1 ml) and anhydrous p-toluene sulfonic acid (1 mg)is added thereto and the mixture stirred vigorously under reflux for 36hours. Water which forms in the ketalization is removed during thisperiod by the aid of a Dean and Stark moisture test receiver. Saturatedaqueous sodium bicarbonate (2.5 ml) is added to the cooled reactionmixture which is then transferred to separatory funnel where it isdiluted with water (10 ml). The organic layer is separated, the aqueouslayer further extracted (three times, 10 ml) with more benzene, thecombined benzene extract washed with water, dried over potassiumcarbonate and filtered. The solvent is removed under reduced pressure toyield the 13-ethylenedioxy ketal of9,10-dihydro-9-acetyl-6,9,11-trihydroxy-(8H)naphthacene-6,9,11-triacetate(XXVIa).

The residue is then taken up in a mixture of acetic anhydride (5 ml) andpyridine (5 ml) and the resultant solution allowed to stand at ambienttemperature overnight. The mixture is poured onto ice water andextracted with benzene. The benzene layer is washed with 2N aqueoushydrochloric acid and saturated sodium bicarbonate and then the solventremoved under reduced pressure. This procedure will re-acylate any ofthe hydroxy groups which have become de-acylated during the ketalizationstep.

EXAMPLE XXI(±)-DEMETHOXY-7-OXO-7-DEOXYDAUNOMYCINONE-6,9,11-TRIACETATE-13-ETHYLENEKETAL (XXVIIa)

A mixture of chromium trioxide (21 mg) in glacial acetic acid (1.0 ml)is added to a solution of7,10-dihydro-6,9,11-trihydroxy-9-acetal-(8H)naphthacene-6,9,11-triacetate-13-ethyleneketal (XXVIa) (14 mg) in glacial acetic acid (1 ml) at room temperatureunder nitrogen. The mixture is stirred at room temperature for 16 hours,diluted with water, and extracted with chloroform. The chloroformextract is thoroughly washed with water and dried over anhydrous sodiumsulfate. The solvent is removed under reduced pressure to give an oilyresidue. The residue is chromatographed on silica gel preparative TLCplates, elution with methanol in methylene chloride (1:99)yields(±)4-demethoxy-7-oxo-7-deoxydaunomycinone-6,9,11-triacetate-13-ethyleneketal (XXVIIa).

EXAMPLE XXII (±)-4-DEMETHOXYDAUNOMYCINONE (XXVa)

To isopropanol (5 ml) is added sodium hydroxide (10 mg) and sodiumborohydride (20 mg) with cooling. To this solution is added a solutionof(±)4-demethoxy-7-oxo-7-deoxydaunomycinone-6,9,11-triacetate-13-ethyleneketal (XXVIIa) (0.5 mmole) in isopropanol (2 ml). The reaction mixtureis heated to reflux and allowed to stand, in an inert atmosphere,overnight. The reaction mixture is then diluted with aqueous sodiumhydroxide (1N, 10 ml) and extracted with chloroform. The extract iswashed with water, dried over anhydrous sodium sulfate, and evaporatedto yield a residue which is taken up in trifluoroacetic acid (5 ml) andthe solution allowed to stand for two hours at room temperature. Thereaction mixture is poured into water, extracted with chloroform, thechloroform washed well with water, and then dried over sodium sulfate.

The residue is dissolved in aqueous hydrochloric acid (1N, 5 ml) and thesolution heated for two hours on a steam bath. After basification withconcentrated aqueous ammonium hydroxide, the solution is extracted withmethylene chloride (four times, 5 ml), the combined extract washed withwater (two times, 5 ml), dried over sodium sulfate and evaporated underreduced pressure to yield a residue, which on chromatography on silicaprep plate (elution with 3% methanol/methylene chloride) gives(±)-4-demethoxydaunomycinone (XXVa) as the major product.

EXAMPLE XXIII

The procedures of Examples XX through XXII may be carried out with anyof the naphthacenequinones produced in accordance with Example XV toprovide (±)-daunomycinone, (±)-1-methoxy-4-demethoxydaunomycinone, andthe corresponding (±)-4-butoxy-(and 1-butoxy)-; 4-methyl-(and1-methyl)-; 4-chloro-(and 1-chloro)-; 4-bromo-(and 1-bromo)-; 4-benzyl-(and 1-benzyl)-; 4-chlorobenzyl-(and 1-chlorobenzyl)-; 1,4-diethyl-;1,4-dichloro-; 1.4-dibenzyl-; 2-butyl-(and 3-butyl)-; 2-methyl-(and3-methyl)-; 2-chloro-(and 3-chloro)-; 2,3-dimethyl-; 2,3-dibromo-; and2,3-dibenzyl-9-acetyl-6,9,11-trihydroxy-7,10-dihydro-5,12-(8H)naphthacenedione(XXVb).

EXAMPLE XXIV DIRECT RESIN OXIDATION OF9-ETHYNYL-7,10-DIHYDRO-6,9,11-TRIHYDROXY-5,12-(8H)NAPHTHACENEDIONE

9-Ethynyl-7,10-dihydro-6,9,11-trihydroxy-5,12-(8H)naphthacenedione (500mg) was suspended in methanol (125 ml) and water (25 ml). Mercury(II)-Resin (5 g, prepared by the method of M. S. Newman, JACS, 75, 4740(1953), substituting Amberlite CG-120 for Dowex-50) was added, and thereaction was heated at reflux with stirring and monitored by tlc untilno starting material remained (approximately 20 hours). The reactionmixture was filtered, and the filter cake was washed with chloroformuntil all colored material was removed. The filtrate was poured intowater, the two phases were separated, and the aqueous phase wasextracted with several portions of chloroform. The combined extractswere washed with water and saturated saline, dried over sodium sulfate,and the solvent was removed under reduced pressure. Chromatography oversilica gel (˜250 g) eluting with methylene chloride and graduallychanging to methanol/methylene chloride (3:97) yielded(±)-4-demethoxy-7-deoxydaunomycinone (460 mg).

In accordance with the above procedure but where, in place of9-ethynyl-7,10-dihydro-6,9,11-trihydroxy-5,12-(8H)naphthacenedione,there is utilized the corresponding 4-methoxy-(or 1-methoxy)-;4-butoxy-(and 1-butoxy)-; 4-methyl-(and 1-methyl)-; 4-chloro-(and1-chloro)-; 4-bromo-(and 1-bromo)-; 4-benzyl-(and 1-benzyl)-;4-chlorobenzyl-(and 1-chlorobenzyl)-; 1,4-diethyl-; 1,4-dichloro-;1,4-dibenzyl-; 2-butyl-(and 3-butyl-; 2-methyl-(and 3-methyl)-;2-chloro-(and 3-chloro)-; 2,3-dimethyl-; 2,3-dibromo-; and2,3-dibenzyl-9-ethynyl-6,9,11-trihydroxy-7,10-dihydro-5,12-(8H)-naphthacenedioneto yield (±)-7-deoxydaunomycinone (and its 1-methoxy regioisomer) andthe corresponding (±)-4-butoxy-(and 1-butoxy)-; 4-methyl-(and1-methyl)-; 4-chloro-(and 1-chloro)-; 4-bromo-(and 1-bromo)-;4-benzyl-(and 1-benzyl)-; 4-chlorobenzyl-(and 1-chlorobenzyl)-;1,4-diethyl-; 1,4-dichloro-; 1,4-dibenzyl-; 2-butyl-(and 3-butyl)-;2-methyl-(and 3-methyl)-; 2-chloro-(and 3-chloro)-; 2,3-dimethyl-;2,3-dibromo-; and 2,3-dibenzyl-4-demethoxy-7-deoxydaunomycinone.

EXAMPLE XXV RESOLUTION OF (±)-DEMETHOXY-7-DEOXYDAUNOMYCINONE (XXIVa)

(±)-4-Demethoxy-7-deoxydaunomycinone (10 mg) and(R)-2-aminoxy-4-methylvaleric acid (5 mg) were suspended in amethanol-pyridine (10:1) mixture (2.5 ml). The mixture was stirred atroom temperature for 24 hours, then poured into 0.1 N hydrochloric acidand extracted with chloroform. The extracts were combined, washed withwater, dried over anhydrous sodium sulfate, and the solvent was removedunder reduced pressure. The residue was spotted on a thin tlc plate andeluted three times with 1% glacial acetic acid in 3% methanol/methylenechloride (3:97) to give two product bands.

Each of the two oximes obtained by the above procedure was hydrolyzed bythe following procedure:

The oxime was dissolved in trifluoroacetic acid (2 ml) and treated with37% formaldehyde (1 ml). The reaction was stirred at room temperaturefor five hours, then poured into water and extracted with chloroform.The combined extracts were washed with saturated sodium bicarbonate,water, and dried over anhydrous sodium sulfate. Mass spectra and tlcshow the material to be 4-demethoxy-7-deoxydaunomycinone.

CD spectra of the two compounds show that the less polar oxime has 9(S)stereochemistry.

The foregoing procedure may be carried out with any of thenaphthacenequinones produced in accordance with Example XIX or XXIV toprovide, in resolved form, the stereoisomers of 7-deoxydaunomycinone(and its 1-methoxy regioisomer) and the corresponding 4-butoxy-(and1-butoxy)-; 4-methyl-(and 1-methyl)-; 4-chloro-(and 1-chloro)-;4-bromo-(and 1-bromo)-; 4-benzyl-(and 1-benzyl)-; 4-chlorobenzyl-(and1-chlorobenzyl)-; 1,4-diethyl-; 1,4-dichloro-; 1,4-dibenzyl-;2-butyl-(and 3-butyl)-; 2-methyl-(and 3-methyl)-; 2-chloro-(and3-chloro)-; 2,3-dimethyl-; 2,3-dibromo-; and2,3-dibenzyl-9-acetyl-6,9,11-trihydroxy-7,10-dihydro-5,12-(8H)naphthacenedione(XXIV).

We claim:
 1. A compound of the formula ##STR4## wherein R₆ is loweralkanoyl or phenyl lower alkanoyl,R₇ is hydrogen, lower alkyl, orhalogen of the group chlorine or bromine, R₉ is hydrogen, lower alkyl,or lower alkoxy, phenyl- or substituted phenyl lower alkyl wherein thesubstituent groups are lower alkyl, lower alkoxy or halo, wherein thepartial term "lower alk" signifies a straight or branch chainhydrocarbon moiety containing 1 to 5 carbon atoms in the chain, orhalogen of the group chlorine or bromine, provided that where one R₉moiety is lower alkoxy, the other R₉ moiety has one of the alternatevalues given hereinabove, further provided that where both R₇ groups areother than hydrogen, R₉ is hydrogen and where R₉ is other than hydrogen,R₇ is hydrogen.
 2. A compound of claim 1 wherein R₇ = R₉ = hydrogen andR₆ = acetyl.
 3. A compound of claim 1 wherein R₇ is hydrogen, one R₉moiety is lower alkoxy and the other R₉ moiety is hydrogen.
 4. Acompound of claim 1 wherein R₇ is lower alkyl and R₉ is hydrogen.
 5. Acompound of claim 1 wherein R₇ is methyl and R₉ is hydrogen.
 6. Acompound of claim 1 wherein R₇ is hydrogen and R₉ is lower alkyl.
 7. Acompound of claim 1 wherein R₇ is hydrogen and R₉ is methyl.